Summary
We studied the inhibitory effect of pentosan polysulphate (PPS, Hémoclar®) on thrombin
formation in blood coagulation. In contrast to a current hypothesis (1) the anti thrombin
III independent effect of PPS on blood coagulation is not caused by preventing the
binding of the factors IX, IXa, X, Xa, VIII, V, Va and II onto procoagulant phospholipids.
We investigated the activation by thrombin of factors I, V and VIII. A strong inhibitory
effect of PPS on factor VIII activation could be observed. Inhibition of the activation
of factor V to the same extent requires about 30-fold higher concentrations of PPS,
whereas the activation (clotting) of fibrinogen is not inhibited. The effect of PPS
on factor VIIIa is two-fold: A) it inhibits its formation and B) it inhibits its function probably
by the formation of a factor VIIIa-PPS complex.
Prothrombinase, constituted of purified factors Xa, Va and phospholipids was not inhibited by PPS, neither were incomplete forms of this
enzyme, lacking phospholipids or factor Va. The complete factor X activating enzyme (factors IXa, VIIIa and phospholipids), however, was strongly inhibited, but incomplete forms, lacking
factor VIII, were not. The inhibition of the complete enzyme can be explained by reversible
binding of PPS to factor VIIIa (causing an inhibition of its function) and it is not an effect on the enzymatic
function of the complete enzyme. On saturation of the enzyme with an excess of factor
VIIIa no inhibition by PPS is noticed.
We postulate therefore that the antithrombin III independent inhibitory effect of
PPS on thrombin generation on blood coagulation is by interaction with factor VIIIa. This effect is additional to the heparin-like action of PPS, i.e. potentiation of
the activity of antithrombin III and/or heparin cofactor II. At concentrations attained
during therapeutic use the action of pentosan polysulphate on factor VIIIa is the only one that will significantly inhibit the coagulation mechanism.
Keywords
Pentosan polysulphate - Blood coagulation
